Hydroxy-ketones of pregnane series



Patented Nov. 25, 1941 .HYDROXY-KETONES OF PREGNANE SERIES Tadeus Reichstein, Zurich, Switzerland, assignor, by mesne assignments, to Roche-Organon, Inc., Nutlcy, N. J., a corporation of New Jersey No Drawing. Application January 20, 1938, Se-

rial No. 186,006. In the Netherlands January 6 Claims.

degradation of the side-chain in cholanic acid. 10

It has now been found that the oxydative degradation is also possible with a-[cyclopentanodimethyl-po1yhydro-phenanthrol;lv propionic acids, in the ring-system of which further hydroxyl groups are substituted. In this way the above ketones are obtained.

It was found that not only a-[cyclopentanodimethyl-perhydro-phenanthroll -propionic acids but also unsaturated a-[cyclopentano-dimethylpolyhydro-phenanthrol]-propionic acids with a double bond in the ring-system are suitable for this reaction provided that, before treatment with oxidantsa halogen or a hydrogen halide, which can be removed from the degradation products, is added to the double bond.

Not only is it possible in this way to prepare substances hitherto rare or unknown but also the yield is relatively large. Such was not to be expected especially in view of the number of substituents in the ring-system. So substances which may be used for the synthesis of therapeutically active substances will become less expensive.

The course of the reaction is elucidated by the following scheme:

0 H 0 Ac CH3 CH3 CH OH; I H: I

CH C\ /R1 p C O O R i A11:\J p 1 OH HO OH -r A O OAc Acylation Grignardation [R=H or alkyl] 0 A 0 Ac 7 0H; CH: CH: I

(Cl. {Milk-397.4)

It is however possible. to increase the yield of [methyl cyclopentano methyl polyhydropolyoxy-phenanthrene]-ketones still further. In this case not one of the substituted propionic acids described above is used as a starting material but higher fatty acids substituted in t .e same way; however, the C-atom C20 must ,always bear one CI-Is-group.

These substances, whether or not esterified, are submitted to an analogous treatment such as application of Grignards reaction, acylation, if desired splitting off of water [when a double bond is present in a ring it must be protected by the addition of a halogenor of a hydrogen halide] and oxidation after which the halogenor hydrogen halide is removed again. This treatment is repeated as long as any ketones are formed. The ketones formed by the successive oxidations are separated and, according to known methods, saponified and purified. e

Example.--200 g. of cholic acid are methylated according to Werner [diss. Miinchen, 1937] in methanol with hydrochloric acid and recrystallised from methanol. Yield 171 g. [M. P. 156-158 com].

45 g. of ester are dissolved in 200 cm. benzene and gradually added to an ethereal solution of a Grignard-compound prepared from 25 g. Mg and g. CHaI. The mixture is boiled with re-l flux for 6 hours on the water-bath and poured into 1 kg. of ice and cm. concentrated H01. The product of the reaction is extracted with ethyl-acetate, acidified, washed until neutral reaction and the solvent is distilled in vacuo. The residueis saponified in alkaline methanol whereupon water is added; the methanol is evaporated in vacuo and the residue is extracted with ethylacetate. The solvent is evaporated again and the residue crystallised from methanol. The yield is 25 g. of dimethyl-3,7,12-trihydroxy-norcholyl-carb-inol [M. P. 184-185" C. corn]. From the mother-liquor further 15 g. may be prepared as a hydrate by evaporation and addition of acetone.

64 g. of carbinol are heated for 18 hours on a boiling water-bath with 300 cm. dry pyridine and 300 cm. freshly distilled acetic anhydride, then evaporated to dryness in vacuo at 60 C. and shaken with water and ether. The ethereal solution is washed with dilute HCl and NazCOssolution and evaporated to dryness; 92 g. of crude product remain. By recrystallisation 47 g. of dimethyl-3,7,12-triacetoXy-nor-cholyl-carbinol-acetate [M. P. 108.5-112" C.] are obtained and from the mother-liquor further 23 g. of this substance are obtained [M. P. 105-111 C.l. 90 g. of tetra-acetylcarbinol are oxidized with 61 g. of CrO3 in glacial acetic acid. In this way 17 g. of neutral substances and 57 g. of crude acid are obtained. From the neutral fraction 10 g. of ketones may be separated; bymeans of Girards reagent; 6.3 g. of ketone-free substances remain.

By recrystallisation, etc., from the crude acid 32 g. of crystalline nor-cholic acid are obtained as well as 1.8. g. of bis-nor-cholic-acid [M. P. 298-304 C.] whereas after saponifieation of the residual resinous acid 11 g. of crystnor-cholic- I acid are obtained. 12 g. of tri-acetyl-hor-cholicacid are saponified with 7.5 g. of'KOH. On acidifying 7.5 g. of the hydrate [1st M. P. 147-150 C., 2nd M. P. 172 C.] precipitate. From the motherliquor further 2 g. of nor-cholic-acid may be obtained. The nor-cholic acid is well dried whereafter its M. P. is 188-192 C. corr.

[a] =+59.4 [c=0.4711 in abs. ethanol] 7 g. of nor-cholic-acid are subjected to a treatment analogous to that describedabove. for cholic acid. In this manner 5.5 g. of methylester [M. P. 159-16l C. corn] are obtained from 7 g. of nor-cholic acid. By treatment with methyl-magnesium-bromide 4 g. of dimethyl- [3, 7, 12-trihydroxy bis nor-cholyl] carbinol [M. P. 238-242 C. corn] are obtained from g. of nor-cholic-methylester. After acetylation the melting point is 129-131 C.

5 g. of this tetra-acetate are oxidized with 3.5 g. of CIO3 after which 1.3 g. of neutral fraction and 2.7 g. of resinous acid are obtained. From the neutral fraction 0.8 g. of ketones and 0.5 g. of ketone-free fraction may be separated by means of Girards reagent. The acetylated resinous acid [2.7 g.] is saponified with alkali in which way 1.1 g. of bis-nor-cholic acid [M. P. 285-296 C. corr.] are obtained.

4.9' g. of bis-nor-cholic acidare treated as describedfor cholic acid. In the first phase 2.9g. of niethylester are obtained [1st M. P.. 97- 98"; 2nd M. P. 156-159 C.] [a] =+22O [0:0544'8 in abs. ethanol]. 4.1 g. of bis-nor-cholic-methylester are treated with a Grignards solution prepared from 4.2 g. of Mg and 28 g. of CsHsBl and 3.8 g. of carbinol are obtained which are acetyl-- ated. In this way 3 g. of a crystalline product are formed [M. P. 252 C. corn].

[a] =+23.11 [c=0.64=9 in abs. ethanol] 2.2 g. oftri-acetylcarbinol are boiled for 6 hours in glacial acetic acid by which water is splitted off. From the residue 1.7 g. of 1.1-diphenylmethyl- [3,7,12-triacetoxy-aetiocholyl] ethylene [M. P. 182-183 C. corr.] can; be obtained.

[a] =+423.6 [c .0.5265 in abs. ethanol] 1.25 g. of this substance solved in s em.. 'CI-I'C13 are ozonized at 0 C. for minutes [corresponding to 0.28 g. 03 instead of 0.1 gflaccorde ing to theory]. The chloroform is eliminated,

30 cm. of glacial acetic acid and zinc-splinters are added and the mixture is heated on the water-bath until potassium-iodide-starchpaper is no longer coloured blue. Then the mixture is evaporated to dryness in vacuo and shaken with water and ether; the ethereal solution is washed with dilute HCl and NazCos-solution. After evaporation of the solvent 1.4' g. of a colourless oil remain which are boiled for 2-3 minutes with 3 g. of Girards reagent T, 20 cm. of methanol and 1 cm. glacial acetic acid. The mixture is slowly cooled to room temperature and subsequently cooled with a refrigerant mixture. Then an ice-cold mixture of 18 cm. 2NNa2CO3 and 12 cm. H2O is added whereupon the whole is 3 times extracted with ether at 0 C. Now the aqueous layer is acidified to Congo with HCl and 3 times extracted with ether at room temperature. The ethereal layers are washed with soda until neutral reaction, the ether is evaporated and" 0.6 g. ofJketon'e: remain as a. colourless oi'l. The latter is solved in a small amount'of ether and pentane is added; until turbidity occurs. After a few hours 545- mg. of crystalline 3,7,l3-triacetoxy-pregnane- 20-on may be" filtered oil with suction [M. P; 132-134 C.] a']' =120'.7 [0:033 in abs. ethanol]. This substance is very hygroscopic and easily soluble in most, of the organic solvents except petroleumether.

400 mg. of triacetyl'ketone are boiled with reflux for 6 hours with 6- mols methyl-alcoholicpotassium-hydrox-ide. Water is added and the methanol evaporated in vacuo. The residue is 3 times rapidly shaken at 0 C. with pure ethylacetate. The extracts arewashed with a small amount of water dried over sulfate and-evaporated in vacuo. A viscous weakly yellow syrup remains which may be: crystallized from acetone. Yield mg. M. P; -127 C. with de-- composition [splitting off of water]. Thewaterfree ketone was not crystal'lisable and is ex'-- tremely hygroscopic. [a] =+10-7.75 [c'=0.1l'23 in abs. ethanol]. The 3,7,12-trioxy-pregnane- 20-on is rather sparingly soluble in ether and:

benzene and easily solublein methanol, ethanol, glacial acetic acid and ethyl acetate.-

It isto be understood that the above example will elucidate the-invention but that the same is not limited thereto.

What I claim is:

1. Compounds of the cyclopentano-dimethyl-- polyhydrophenanthrene series having aside chain of the form CO.CII3 at the carbonatom C11 and having a single substituent selected-fromthe class consisting of hydroxyl and a group convertible into a hydroxyl group by means of hydrolysis in each of more than one of the rings of the polyhydro-phenanthrene nucleus.

2. The cyclopentano-dimethyl polyhydrophenanthrene derivatives having a side chain of the form -CO.CH3 at the carbon atom C17 and having a single substituent from the class consisting of hydroxyl and acyloxyl ineach of more thanone of the rings of the polyhydrophenanthrene nucleus.

3. The cyclopentano-dimethyl polyhydrophenanthrene derivatives having a side chain of the form -CO.CH3 at the carbon atom C1 and having a singlesubstituent from the class consisting of hydroxyl and acyloxyl at each of the carbon atoms C7 andCiz;

4. The cyclopjentano-dimethyl polyhydrophenanthrene derivatives having a side chain of the term-CODE; at the carbon atom C17 and having a. single substituent from the class consisting of hydroxyl and acyloxyl at each of the carbon atoms C3, C1, and C12.

5. As a new compound trihydroxy-3,'7,12e pregnanone-20, the hydrate of which having a melting point of 120127 C. [a] =+107.8 [c=0.1123 in abs. ethanol] and the structure CH; CHa

3-0 O---CH: OH

TADEUS REIC HSTEIN. 

